Benzimidazole inhibitors of leukotriene production

ABSTRACT

The present invention relates to compounds of formula (IA), (IB) and (IC): 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, wherein R 1 -R 7  are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

FIELD OF THE INVENTION

This invention relates to benzimidazoles that are useful as inhibitorsof five lipoxygenase activating protein (FLAP) and are thus useful fortreating a variety of diseases and disorders that are mediated orsustained through the activity of leukotrienes including asthma,allergy, rheumatoid arthritis, multiple sclerosis, inflammatory pain,acute chest syndrome and cardiovascular diseases includingatherosclerosis, myocardial infarction and stroke. This invention alsorelates to pharmaceutical compositions comprising these compounds,methods of using these compounds in the treatment of various diseasesand disorders, processes for preparing these compounds and intermediatesuseful in these processes.

BACKGROUND OF THE INVENTION

Leukotrienes (LTs) and the biosynthetic pathway from arachidonic acidleading to their production have been the targets of drug discoveryefforts for over twenty years. LTs are produced by several cell typesincluding neutrophils, mast cells, eosinophils, basophils monocytes andmacrophages. The first committed step in the intracellular synthesis ofLTs involves oxidation of arachidonic acid by 5-lipoxygenase (5-LO) toLTA4, a process requiring the presence of the 18 kD integral membraneprotein 5-lipoxygenase-activating protein (FLAP) (D. K. Miller et al.,Nature, 1990, 343, 278-281; R. A. F. Dixon et al., Nature, 1990, 343,282-284). Subsequent metabolism of LTA₄ leads to LTB₄, and the cysteinylLTs-LTC₄, LTD₄ and LTE₄ (B. Samuelsson, Science, 1983, 220, 568-575).The cysteinyl LTs have potent smooth muscle constricting andbronchoconstricting effects and they stimulate mucous secretion andvascular leakage. LTB₄ is a potent chemotactic agent for leukocytes, andstimulates adhesion, aggregation and enzyme release.

Much of the early drug discovery effort in the LT area was directedtowards the treatment of allergy, asthma and other inflammatoryconditions. Research efforts have been directed towards numerous targetsin the pathway including antagonists of LTB₄ and the cysteinylleukotrienes LTC₄, LTD₄ and LTE₄, as well as inhibitors of5-lipoxygenase (5-LO), LTA₄ hydrolase and inhibitors of 5-lipoxygenaseactivating protein (FLAP) (R. W. Friesen and D. Riendeau, LeukotrieneBiosynthesis Inhibitors, Ann. Rep. Med. Chem., 2005, 40, 199-214). Yearsof effort in the above areas have yielded a few marketed products forthe treatment of asthma including a 5-LO inhibitor, zileuton, and LTantagonists, montelukast, pranlukast and zafirlukast.

More recent work has implicated LTs in cardiovascular disease, includingmyocardial infarction, stroke and atherosclerosis (G. Riccioni et al.,J. Leukoc. Biol., 2008, 1374-1378). FLAP and 5-LO were among thecomponents of the 5-LO and LT cascade found in atherosclerotic lesions,suggesting their involvement in atherogenesis (R. Spanbroek et al.,Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 1238-1243). Pharmacologicalinhibition of FLAP has been reported to decrease atherosclerotic lesionsize in animal models. In one study, oral dosing of the FLAP inhibitorMK-886 to apoE/LDL-R double knockout mice fed a high-fat diet from 2months of age to 6 months led to a 56% decrease in plaque coverage inthe aorta and a 43% decrease in the aortic root (J. Jawien et al., Eur.J. Clin. Invest., 2006, 36, 141-146). This plaque effect was coupledwith a decrease in plaque-macrophage content and a concomitant increasein collagen and smooth muscle content which suggests a conversion to amore stable plaque phenotype. In another study, it was reported thatadministration of MK-886 via infusion to ApoE^(−/−)xCD4dnTβRII mice(apoE KO mice expressing a dominant-negative TGF-beta receptor whicheffectively removes all TGF-beta from the system) resulted in about a40% decrease in plaque area in the aortic root (M. Back et al., Circ.Res., 2007, 100, 946-949). The mice were only treated for four weeksafter plaque growth was already somewhat mature (12 weeks) thus raisingthe possibility of therapeutically treating atherosclerosis via thismechanism. In a study examining human atherosclerotic lesions, it wasfound that the expression of FLAP, 5-LO and LTA₄ hydrolase wassignificantly increased compared to healthy controls (H. Qiu et al.,Proc. Natl. Acad. Sci. U.S.A., 103, 21, 8161-8166). Similar studiessuggest that inhibition of the LT pathway, for example by inhibition ofFLAP, would be useful for the treatment of atherosclerosis (for reviews,see M. Back Curr. Athero. Reports, 2008 10, 244-251 and Cum Pharm. Des.,2009, 15, 3116-3132).

In addition to the work cited above, many other studies have beendirected towards understanding the biological actions of LTs and therole of LTs in disease. These studies have implicated LTs as having apossible role in numerous diseases or conditions (for a review, see M.Peters-Golden and W. R. Henderson, Jr., M. D., N. Engl. J. Med., 2007,357, 1841-1854). In addition to the specific diseases cited above, LTshave been implicated as having a possible role in numerous allergic,pulmonary, fibrotic, inflammatory and cardiovascular diseases, as wellas cancer. Inhibition of FLAP is also reported to be useful for treatingrenal diseases such as diabetes-induced proteinuria (see for example J.M. Valdivieso et al., Journal of Nephrology, 2003, 16, 85-94 and AMontero et al., Journal of Nephrology, 2003, 16, 682-690).

A number of FLAP inhibitors have been reported in the scientificliterature (see for example J. F. Evans et al., Trends inPharmacological Sciences, 2008, 72-78) and in U.S. patents. Some havebeen evaluated in clinical trials for asthma, including MK-886, MK-591,and BAY X1005, also known as DG-031. More recently, the FLAP inhibitorAM-103 (J. H. Hutchinson et al., J. Med. Chem. 52, 5803-5815) has beenevaluated in clinical trials, based on its anti-inflammatory properties(D. S. Lorrain et al., J. Pharm. Exp. Ther., 2009,DOI:10.1124/jpet.109.158089). Subsequently, it was replaced by theback-up compound AM-803 (GSK-2190915) for the treatment of respiratorydiseases. DG-031 has also been in clinical trials to evaluate its effecton biomarkers for myocardial infarction risk and showed a dose-dependentsuppression of several biomarkers for the disease (H. Hakonarson et al.,JAMA, 2005, 293, 2245-2256). MK-591 was shown in a clinical trial toreduce proteinuria in human glomerulonephritis (see for example A. Guashet al., Kidney International, 1999, 56, 291-267).

However, to date, no FLAP inhibitor has been approved as a marketeddrug.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds which inhibit5-lipoxygenase activating protein (FLAP) and are thus useful fortreating a variety of diseases and disorders that are mediated orsustained through the activity of leukotrienes, including allergic,pulmonary, fibrotic, inflammatory and cardiovascular diseases andcancer. This invention also relates to pharmaceutical compositionscomprising these compounds, methods of using these compounds in thetreatment of various diseases and disorders, processes for preparingthese compounds and intermediates useful in these processes.

DETAILED DESCRIPTION OF THE INVENTION

In its first broadest embodiment, the present invention relates to acompound of formula IA

wherein:

R¹ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl,imidazopyridinyl, pyrazolopyridinyl or dihydropyrrolopyridinyloptionally substituted with oxo, wherein each heterocycle is optionallyindependently substituted with one to three groups selected from Ra, Rband Rc;

R² is C₁-C₆ alkyl or C₃₋₆ cycloalkyl optionally substituted with C₁₋₃alkyl;

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR^(S), —C(O)NR⁸R⁹ or 5-6membered heteroaryl ring which is optionally substituted with C₁₋₃alkyl;

R⁴, R⁵, and R⁶ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)_(n)C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k)-5 (O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a 5-6 membered heterocyclic ring;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl, and 5-6membered heterocyclic ring;

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl, and —CH₂—OH;

Rb is selected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH,—C≡N, —CH₂NH₂ and —C(O)OCH₃;

Rc is selected from —H, —CH₃ and —OH;

R¹⁰ and R¹¹ are each independently selected from —H, C₁₋₆alkyl,C₁₋₆alkyl-5-6 membered heterocyclyl, C₁₋₆alkyl-5-6 membered heteroaryloptionally substituted with halogen and C₁₋₆alkyl-aryl;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

In a second embodiment, the present invention relates to a compound offormula (IA) as described in the broadest embodiment above, or apharmaceutically acceptable salt thereof, wherein:

R¹ is selected from:

R² is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the cycloalkyl group is optionally substituted with a C₁₋₃ alkylgroup;

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸, —C(O)NR⁸R⁹, pyrrolyl,furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein the heteroaryl ring isoptionally substituted with C₁₋₃ alkyl;

R⁴, R⁵ and R⁶ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)_(n)C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k) —S(O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,        piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl        and tetrahydropyranyl;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl;

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl and —CH₂—OH;

Rb is selected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH,—C≡N, —CH₂NH₂ and —C(O)OCH₃;

Rc is selected from —H, —CH₃ and, —OH;

R¹⁰ and R¹¹ are each independently selected from —H, C₁₋₆alkyl,C₁₋₆alkyl-5-6 membered heterocyclyl, C₁₋₆alkyl-5-6 membered heteroaryloptionally substituted with fluoro and C₁₋₆alkyl-phenyl;

n is 0, 1 or 2.

In third embodiment, the present invention relates to a compound offormula (IA) as described in any of the preceding embodiments, wherein:

R¹ is selected from:

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl and —CH₂—OH;

Rb is selected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH,—C≡N, —CH₂NH₂ and —C(O)OCH₃;

Rc is selected from —H, —CH₃ and, —OH;

R¹⁰ and R¹¹ are each independently selected from —H, C₁₋₆alkyl,C₁₋₆alkyl-5-6 membered heterocyclyl, C₁₋₆alkyl-fluorpyridine andC₁₋₆alkyl-phenyl;

or a pharmaceutically acceptable salt thereof.

In a fourth embodiment there is provided a compound of formula (IA) asdescribed in any of the preceding embodiments above, wherein:

R² is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,cyclopropyl, cyclobutyl or cyclopentyl, wherein the cycloalkyl group isoptionally substituted with methyl;

or a pharmaceutically acceptable salt thereof.

In a fifth embodiment there is provided a compound of formula (IA) asdescribed in any of the preceding embodiments, wherein:

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR^(S), —C(O)NR⁸R⁹,pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein the heteroaryl ring isoptionally substituted with C₁₋₃ alkyl;

R⁴, R⁵ and R⁶ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)₂C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k) —S(O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,        piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl        and tetrahydropyranyl;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl;

or a pharmaceutically acceptable salt thereof.

In a sixth embodiment there is provided a compound of formula (IA) asdescribed in the first or second embodiment above, wherein:

R¹ is selected from:

R² is t-butyl or cyclobutyl optionally substituted with a methyl group;

R³ is —H, C₁₋₃ alkoxy, —COOR⁸, —C(O)NR⁸R⁹ or triazolyl which isoptionally substituted with a methyl group;

R⁴, R⁵ and R⁶ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl;

R⁸ and R⁹ are each independently selected from —H and C₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

In a seventh embodiment there is provided a compound of formula (IA) asdescribed in the sixth embodiment above, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

In an eighth embodiment there is provided a compound of formula (IA) asdescribed in the sixth embodiment above, wherein:

R² is t-butyl or cyclobutyl optionally substituted with a methyl group;

or a pharmaceutically acceptable salt thereof.

In a ninth embodiment there is provided a compound of formula (IA)according to embodiment six, wherein:

R¹ is

R² is t-butyl;

R³ is selected from

R⁴, R⁵ and R⁶ are each independently selected from —H, —CN, F,cyclopropyl, methoxy and t-butoxy;

or a pharmaceutically acceptable salt thereof.

In a tenth embodiment there is provided a compound of formula (IA)according to embodiment nine above, wherein:

R² is

or a pharmaceutically acceptable salt thereof.

In another first broadest embodiment, the present invention relates to acompound of formula IB

wherein:

R¹ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl,imidazopyridinyl, pyrazolopyridinyl or dihydropyrrolopyridinyloptionally substituted with oxo, wherein each heterocycle is optionallyindependently substituted with one to three groups selected from Ra, Rband Rc;

R² is C₁-C₆ alkyl or C₃₋₆ cycloalkyl optionally substituted with C₁₋₃alkyl;

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR^(S), —C(O)NR⁸R⁹ or 5-6membered heteroaryl ring which is optionally substituted with C₁₋₃alkyl;

R⁵, R⁶, and R⁷ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)_(n)C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k) —S(O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a 5-6 membered heterocyclic ring;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl, and 5-6membered heterocyclic ring;

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl, and —CH₂—OH;

Rb is selected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH,—C≡N, —CH₂NH₂ and —C(O)OCH₃;

Rc is selected from —H, —CH₃ and, —OH;

R¹⁰ and R¹¹ are each independently selected from —H, C₁₋₆alkyl,C₁₋₆alkyl-5-6 membered heterocyclyl, C₁₋₆alkyl-5-6 membered heteroaryloptionally substituted with halogen and C₁₋₆alkyl-aryl;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

In a second embodiment, the present invention relates to a compound offormula (TB) as described in the broadest embodiment above, or apharmaceutically acceptable salt thereof, wherein:

R¹ is selected from:

R² is methyl, ethyl, propyl, isopropyl, dimethylpropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the cycloalkyl group is optionally substituted witha C₁₋₃ alkyl group;

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸, —C(O)NR⁸R⁹, pyrrolyl,furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein the heteroaryl ring isoptionally substituted with C₁₋₃ alkyl;

R⁵, R⁶ and R⁷ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)_(n)C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k) —S(O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,        piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl        and tetrahydropyranyl;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl;

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl, and —CH₂—OH;

Rb is selected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH,—C≡N, —CH₂NH₂ and —C(O)OCH₃;

Rc is selected from —H, —CH₃ and, —OH;

R¹⁰ and R¹¹ are each independently selected from —H, C₁₋₆alkyl,C₁₋₆alkyl-5-6 membered heterocyclyl, C₁₋₆alkyl-fluoropyridine andC₁₋₆alkyl-phenyll;

n is 0, 1 or 2.

In third embodiment, the present invention relates to a compound offormula (IB) as described in any of the preceding embodiments, wherein:

R¹ is selected from:

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl and —CH₂—OH;

Rb is selected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH,—C≡N, —CH₂NH₂ and —C(O)OCH₃;

Rc is selected from —H, —CH₃ and, —OH;

R¹⁰ and R¹¹ are each independently selected from —H, C₁₋₆alkyl,C₁₋₆alkyl-5-6 membered heterocyclyl, C₁₋₆alkyl-fluoropyridine andC₁₋₆alkyl-phenyl; or a pharmaceutically acceptable salt thereof.

In a fourth embodiment there is provided a compound of formula (IB) asdescribed in any of the preceding embodiments above, wherein:

R² is methyl, ethyl, propyl, isopropyl, dimethylpropyl, butyl, t-butylor isobutyl;

or a pharmaceutically acceptable salt thereof.

In a fifth embodiment there is provided a compound of formula (IB) asdescribed in any of the preceding embodiments, wherein:

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸, —C(O)NR⁸R⁹, pyrrolyl,furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein the heteroaryl ring isoptionally substituted with C₁₋₃ alkyl;

R⁵, R⁶ and R⁷ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)₂C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k) —S(O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,        piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl        and tetrahydropyranyl;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl;

or a pharmaceutically acceptable salt thereof.

In a sixth embodiment there is provided a compound of formula (IB) asdescribed in the first or second embodiment above, wherein:

R¹ is selcted from:

R² is t-butyl or dimethylpropyl;

R³ is —H, C₁₋₃ alkoxy, or triazolyl which is optionally substituted witha methyl group;

R⁵, R⁶ and R⁷ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl,    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl,    -   (i) morpholinyl or piperidinyl;

R⁸ and R⁹ are each independently selected from —H and C₁₋₆alkyl;

or a pharmaceutically acceptable salt thereof.

In a seventh embodiment there is provided a compound of formula (IB) asdescribed in the sixth embodiment above, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

In an eighth embodiment there is provided a compound of formula (IB) asdescribed in the sixth embodiment, wherein:

R² is t-butyl or dimethylpropyl;

or a pharmaceutically acceptable salt thereof.

In a ninth embodiment there is provided a compound of formula (IB)according to embodiment six, wherein:

R¹ is

R² is t-butyl or dimethylpropyl;

R³ is selected from

R⁵, R⁶ and R⁷ are each independently selected from —H, —CN, F, Cl, Br,methyl, morpholinyl and methoxy;

or a pharmaceutically acceptable salt thereof.

In a tenth embodiment there is provided a compound of formula (IB)according to embodiment nine above, wherein:

R² is t-butyl;

R³ is selected from

R⁵, R⁶ and R⁷ are each independently selected from —H, methyl and Br;

or a pharmaceutically acceptable salt thereof.

In another first broadest embodiment, the present invention relates to acompound of formula IC

wherein:

R¹ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl,imidazopyridinyl, pyrazolopyridinyl or dihydropyrrolopyridinyloptionally substituted with oxo, wherein each heterocycle is optionallyindependently substituted with one to three groups selected from Ra, Rband Rc;

R² is C₁-C₆ alkyl or C₃₋₆ cycloalkyl optionally substituted with C₁₋₃alkyl;

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR^(S), —C(O)NR⁸R⁹ or 5-6membered heteroaryl ring which is optionally substituted with C₁₋₃alkyl;

R⁴, R⁶, and R⁷ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)_(n)C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k) —S(O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a 5-6 membered heterocyclic ring;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl, and 5-6membered heterocyclic ring;

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl, and —CH₂—OH;

Rb is selected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH,—C≡N, —CH₂NH₂ and —C(O)OCH₃;

Rc is selected from —H, —CH₃ and, —OH;

R¹⁰ and R¹¹ are each independently selected from —H, C₁₋₆alkyl,C₁₋₆alkyl-5-6 membered heterocyclyl, C₁₋₆alkyl-5-6 membered heteroaryloptionally substituted with halogen and C₁₋₆alkyl-aryl;

n is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

In a second embodiment, the present invention relates to a compound offormula (IC) as described in the broadest embodiment above, or apharmaceutically acceptable salt thereof, wherein:

R¹ is selected from:

R² is methyl, ethyl, propyl, isopropyl, dimethylpropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the cycloalkyl group is optionally substituted witha C₁₋₃ alkyl group;

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸, —C(O)NR⁸R⁹, pyrrolyl,furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein the heteroaryl ring isoptionally substituted with C₁₋₃ alkyl;

R⁴, R⁶ and R⁷ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)_(n)C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k) —S(O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,        piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl        and tetrahydropyranyl;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl;

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl, oxo and —CH₂—OH;

Rb is selected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH,—C≡N, —CH₂NH₂ and —C(O)OCH₃;

Rc is selected from —H, —CH₃ and, —OH;

R¹⁰ and R¹¹ are each independently selected from —H, C₁₋₆alkyl,C₁₋₆alkyl-5-6 membered heterocyclyl, C₁₋₆alkyl-fluoropyridine andC₁₋₆alkyl-phenyl;

n is 0, 1 or 2.

In third embodiment, the present invention relates to a compound offormula (IC) as described in any of the preceding embodiments, wherein:

R¹ is selected from:

or a pharmaceutically acceptable salt thereof.

In a fourth embodiment there is provided a compound of formula (IC) asdescribed in any of the preceding embodiments above, wherein:

R² is methyl, ethyl, propyl, isopropyl, dimethylpropyl, butyl, t-butylor isobutyl;

or a pharmaceutically acceptable salt thereof.

In a fifth embodiment there is provided a compound of formula (IC) asdescribed in any of the preceding embodiments, wherein:

R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR^(S), —C(O)NR⁸R⁹,pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein the heteroaryl ring isoptionally substituted with C₁₋₃ alkyl;

R⁴, R⁶ and R⁷ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl optionally substituted with one to three —OH,        fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),    -   (g) C₃₋₆ cycloalkyl    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl    -   (i) —S(O)₂C₁₋₆alkyl,    -   (j) —S(O)₂aryl    -   (k)-5 (O)₂ heterocycle    -   (l) —CO₂R⁸,    -   (m) —SCF₃,    -   (n′) a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,        piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl        and tetrahydropyranyl;

R⁸ and R⁹ are each independently selected from —H, C₁₋₆alkyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl;

or a pharmaceutically acceptable salt thereof.

In a sixth embodiment there is provided a compound of formula (IC) asdescribed in the first or second embodiment above, wherein:

R¹ is selected from:

R² is t-butyl;

R³ is —H or halogen;

R⁴, R⁶ and R⁷ are each independently selected from

-   -   (a) —H,    -   (b) —OH,    -   (c) halogen,    -   (d) —CN,    -   (e) —CF₃,    -   (f) C₁₋₆alkyl;    -   (g) C₃₋₆ cycloalkyl,    -   (h) C₁₋₆alkoxy optionally substituted with one to three —OH,        fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl;    -   or a pharmaceutically acceptable salt thereof.

In a seventh embodiment there is provided a compound of formula (IC) asdescribed in the sixth embodiment above, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is

In an eighth embodiment there is provided a compound of formula (IC) asdescribed in the sixth embodiment, wherein:

R² is t-butyl;

or a pharmaceutically acceptable salt thereof.

In a ninth embodiment there is provided a compound of formula (IC)according to embodiment six, wherein:

R¹ is

R² is t-butyl;

R³ is F;

R⁴, R⁶ and Rare each independently selected from —H, Br and methoxy;

or a pharmaceutically acceptable salt thereof.

The following are representative compounds of the invention which can bemade by the general synthetic schemes, the examples, and known methodsin the art.

TABLE 1 Example # Structure Name 1

6-[5-(2-Amino-pyrimidin-5-yl)- 1-tert-butyl-1H-benzimidazol-2-yl]-5-1,2,4-triazol-1-yl-pyridine- 2-carbonitrile 2

6-[5-(2-Amino-pyrimidin-5-yl)- 1-tert-butyl-1H-benzimidazol-2-yl]-5-(3-methyl-1,2,4-triazol-1- yl)-pyridine-2-carbonitrile 3

6-[5-(2-Amino-pyrimidin-5-yl)- 1-tert-butyl-1H-benzimidazol-2-yl]-5-(5-methyl-1,2,4-triazol-1- yl)-pyridine-2-carbonitrile 4

5-[1-tert-Butyl-2-(6- cyclopropyl-3-1,2,4-triazol-1-yl-pyridin-2-yl)-1H-benzimidazol- 5-yl]-pyrimidin-2-ylamine 5

6-[5-(2-Amino-pyrimidin-5-yl)- 1-(1-methyl-cyclobutyl)-1H-benzimidazol-2-yl]-5-(3-methyl- 1,2,4-triazol-1-yl)-pyridine-2-carbonitrile 6

6-[5-(2-Amino-pyrimidin-5-yl)- 1-(1-methyl-cyclobutyl)-1H-benzimidazol-2-yl]-5-(5-methyl- 1,2,4-triazol-1-yl)-pyridine-2-carbonitrile 7

2-[5-(2-Amino-pyrimidin-5-yl)- 1-tert-butyl-1H-benzimidazol-2-yl]-nicotinic acid methyl esler 8

2-[5-(2-Amino-pyrimidin-5-yl)- 1-tert-butyl-1H-benzimidazol-2-yl]-N-methyl-nicotinamide 9

2-[5-(2-Amino-pyrimidin-5-yl)- 1-tert-butyl-1H-benzimidazol-2-yl]-6-cyano-nicotinic acid methyl ester 10

2-[5-(2-Amino-pyrimidin-5-yl)- 1-tert-butyl-1H-benzimidazol-2-yl]-6-cyano-N-methyl- nicotinamide 11

5-[1-tert-Butyl-2-(6-methoxy- pyridin-2-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine 12

5-(1-tert-Butyl-2-pyridin-2-yl- 1H-benzimidazol-5-yl)-pyrimidin-2-ylamine 13

5-[2-(6-tert-Butoxy-pyridin-2- yl)-1-tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2- ylamine 14

5-[1-tert-Butyl-2-(6-fluoro- pyridin-2-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine 15

{5-[1-tert-Butyl-2-(6-fluoro- pyridin-2-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-yl}-(6-fluoro- pyridin-2-ylmethyl)-amine 16

5-[1-tert-Butyl-2-(3-methoxy- pyridin-2-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine 17

5-[1-tert-Butyl-2-(5-fluoro-2- methoxy-pyridin-4-yl)-1H-benzimidazol-5-yl]-pyrimidin-2- ylamine 18

5-(1-tert-Butyl-2-pyridin-4-yl- 1H-benzimidazol-5-yl)-pyrimidin-2-ylamine 19

5-[2-(2-Bromo-pyridin-4-yl)-1- tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine 20

5-[1-tert-Butyl-2-(2-1,2,4- triazol-1-yl-pyridin-3-yl)-1H-benzimidazol-5-yl]-pyrimidin-2- ylamine 21

5-[1-tert-Butyl-2-(5-fluoro-2- 1,2,4-triazol-1-yl-pyridin-3-yl)-1H-benzimidazol-5-yl]- pyrimidin-2-ylamine 22

5-[1-tert-Butyl-2-(5-chloro-2- 1,2,4-triazol-1-yl-pyridin-3-yl)-1H-benzimidazol-5-yl]- pyrimidin-2-ylamine 23

5-[2-(5-Bromo-2-1,2,4-triazol-1- yl-pyridin-3-yl)-1-tert-butyl-1H-benzimidazol-5-yl]-pyrimidin-2- ylamine 24

5-{1-tert-Butyl-2-[2-(5-methyl- 1,2,4-triazol-1-yl)-pyridin-3-yl]-1H-benzimidazol-5-yl}- pyrimidin-2-ylamine 25

5-{1-tert-Butyl-2-[2-(3-methyl- 1,2,4-triazol-1-yl)-pyridin-3-yl]-1H-benzimidazol-5-yl}- pyrimidin-2-ylamine 26

5-[5-(2-Amino-pyrimidin-5-yl)- 1-tert-butyl-1H-benzimidazol-2-yl]-6-1,2,4-triazol-1-yl- nicotinonitrile 27

5-[2-(5-Bromo-2-1,2,4-triazol-1- yl-pyridin-3-yl)-1-(1,1-dimethyl-propyl)-1H-benzimidazol-5-yl]- pyrimidin-2-ylamine 28

5-[1-tert-Butyl-2-(6-methyl-2- 1,2,4-triazol-1-yl-pyridin-3-yl)-1H-benzimidazol-5-yl]- pyrimidin-2-ylamine 29

5-[1-tert-Butyl-2-(5-methoxy- pyridin-3-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine 30

5-[1-tert-Butyl-2-(6-morpholin- 4-yl-pyridin-3-yl)-1H-benzimidazol-5-yl]-pyrimidin-2- ylamine 31

5-(1-tert-Butyl-2-pyridin-3-yl- 1H-benzimidazol-5-yl)-pyrimidin-2-ylamine 32

5-[1-tert-Butyl-2-(2-methoxy- pyridin-3-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine 33

5-[1-tert-Butyl-2-(2-ethoxy- pyridin-3-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine

In one embodiment, the invention relates to any of the compoundsdepicted in Table 1 above and the pharmaceutically acceptable saltsthereof.

Representative compounds of the invention show activity in the FLAPbinding assay and in the human whole blood LTB₄ production inhibitionassay, described in the assessment of biological properties section, asshown in Table 2.

TABLE 2 hFLAP binding Example# IC₅₀ (nM) hWB IC₅₀ (nM) 1 7.1  30 2 4.2 36 3 5.9  89 4 13 140 5 29 256 6 86 894 7 540 3096  8 620 1703  9 110387 10 138 422 11 46 12 700 13 51 14 279 15 870 16 960 17 58  58 18 450449 19 270 270 20 19 447 21 20 253 22 3.2 116 23 4.0  81 24 23 242 25 12278 26 10  75 27 23 667 28 17 194 29 300 30 180 31 542 32 220 33 34

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of the invention, or thepharmaceutically acceptable derivatives thereof, optionally combinedwith conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

The invention includes the use of any compounds of described abovecontaining one or more asymmetric carbon atoms may occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. Isomers shall be defined as being enantiomersand diastereomers. All such isomeric forms of these compounds areexpressly included in the present invention. Each stereogenic carbon maybe in the R or S configuration, or a combination of configurations.

Some of the compounds of the invention can exist in more than onetautomeric form.

The invention includes methods using all such tautomers.

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₆ alkoxy” is a C₁₋₆ alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl, and alkynyl groupsshall be understood as being branched or unbranched where structurallypossible and unless otherwise specified. Other more specific definitionsare as follows:

The term “alkyl” refers to both branched and unbranched alkyl groups. Itshould be understood that any combination term using an “alk” or “alkyl”prefix refers to analogs according to the above definition of “alkyl”.For example, terms such as “alkoxy”, “alkylthio” refer to alkyl groupslinked to a second group via an oxygen or sulfur atom. “Alkanoyl” refersto an alkyl group linked to a carbonyl group (C═O).

In all alkyl groups or carbon chains, one or more carbon atoms can beoptionally replaced by heteroatoms such as O, S or N. It shall beunderstood that if N is not substituted then it is NH. It shall also beunderstood that the heteroatoms may replace either terminal carbon atomsor internal carbon atoms within a branched or unbranched carbon chain.Such groups can be substituted as herein above described by groups suchas oxo to result in definitions such as but not limited to:alkoxycarbonyl, acyl, amido and thioxo. As used herein, “nitrogen” and“sulfur” include any oxidized form of nitrogen and sulfur and thequaternized form of any basic nitrogen. For example, for a —S—C₁₋₆ alkylradical, unless otherwise specified, shall be understood to include—S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆ alkyl.

The term “C₃₋₁₀ carbocycle” or “cycloloalkyl” refers to a nonaromatic 3to 10-membered (but preferably, 3 to 6-membered) monocyclic carbocyclicradical or a nonaromatic 6 to 10-membered fused bicyclic, bridgedbicyclic, or spirocyclic carbocyclic radical. The C₃₋₁₀ carbocycle maybe either saturated or partially unsaturated, and the carbocycle may beattached by any atom of the cycle which results in the creation of astable structure. Non-limiting examples of 3 to 10-membered monocycliccarbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, andcyclohexanone. Non-limiting examples of 6 to 10-membered fused bicycliccarbocyclic radicals include bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane,and bicyclo[4.4.0]decanyl (decahydronaphthalenyl). Non-limiting examplesof 6 to 10-membered bridged bicyclic carbocyclic radicals includebicyclo [2.2.2]heptanyl, bicyclo[2.2.2]octanyl, andbicyclo[3.2.1]octanyl. Non-limiting examples of 6 to 10-memberedspirocyclic carbocyclic radicals include but are not limited tospiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl.

The term “C₆₋₁₀ aryl” refers to aromatic hydrocarbon rings containingfrom six to ten carbon ring atoms. The term C₆₋₁₀ aryl includesmonocyclic rings and bicyclic rings where at least one of the rings isaromatic. Non-limiting examples of C₆₋₁₀ aryls include phenyl, indanyl,indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl,naphthyl, benzocycloheptanyl and benzocycloheptenyl.

The term “5 to 11-membered heterocycle” refers to a stable nonaromatic4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6to 11-membered fused bicyclic, bridged bicyclic or spirocyclicheterocyclic radical. The 5 to 11-membered heterocycle consists ofcarbon atoms and one or more, preferably from one to four heteroatomschosen from nitrogen, oxygen and sulfur. The heterocycle may be eithersaturated or partially unsaturated. Non-limiting examples of nonaromatic4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl,azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl,thiomorpholinyl, 1,1-dioxothiomorpholinyl, morpholinyl, piperidinyl,piperazinyl, and azepinyl. Non-limiting examples of nonaromatic 6 to11-membered fused bicyclic radicals include octahydroindolyl,octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limitingexamples of nonaromatic 6 to 11-membered bridged bicyclic radicalsinclude 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and3-azabicyclo[3.2.1]octanyl. Non-limiting examples of nonaromatic 6 to11-membered spirocyclic heterocyclic radicals include7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and7-aza-spiro[3,4]octanyl.

The term “5 to 11-membered heteroaryl” shall be understood to mean anaromatic 5 to 6-membered monocyclic heteroaryl or an aromatic 7 to11-membered heteroaryl bicyclic ring where at least one of the rings isaromatic, wherein the heteroaryl ring contains 1-4 heteroatoms such asN, O and S, Non-limiting examples of 5 to 6-membered monocyclicheteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl,thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, and purinyl. Non-limiting examples of 7 to 11-memberedheteroaryl bicyclic heteroaryl rings include pyrrolopyridinyl,imidazopyridinyl, pyrazolopyridinyl, dihydropyrrolopyridinyl,benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl,quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl,benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl andbenzothiazolyl.

It will be understood that one to three carbon ring moieties in the eachof the C₃₋₁₀ carbocyclic rings, the 5 to 11-membered heterocyclic rings,the nonaromatic portion of the bicyclic aryl rings, and the nonaromaticportion of the bicyclic heteroaryl rings can independently be replacedwith a carbonyl, thiocarbonyl, or iminyl moiety, i.e., —C(═O)—, —C(═S)—and —C(═NR⁸)—, respectively, where R⁸ is as defined above. The term“heteroatom” as used herein shall be understood to mean atoms other thancarbon such as O, N, and S.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine. Thedefinitions “halogenated”, “partially or fully halogenated”; partiallyor fully fluorinated; “substituted by one or more halogen atoms”,includes for example, mono, di or tri halo derivatives on one or morecarbon atoms. For alkyl, a non-limiting example would be —CH₂CHF₂, —CF₃etc.

Each alkyl, carbocycle, heterocycle or heteroaryl, or the analogsthereof, described herein shall be understood to be optionally partiallyor fully halogenated.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the inventive methodsdisclosed herein.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula IA, IB or IC. A “pharmaceutically acceptablederivative” refers to any pharmaceutically acceptable salt or ester, orany other compound which, upon administration to a patient, is capableof providing (directly or indirectly) a compound useful for theinvention, or a pharmacologically active metabolite or pharmacologicallyactive residue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the invention.

Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the invention. Prodrugs include those compounds that, uponsimple chemical transformation, are modified to produce compounds of theinvention. Simple chemical transformations include hydrolysis, oxidationand reduction. Specifically, when a prodrug is administered to apatient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

The compounds of formula IA, IB or IC may be made using the generalsynthetic methods described below, which also constitute part of theinvention.

General Synthetic Methods

The compounds of the invention may be prepared by the methods describedbelow. In each of the schemes below, the groups R¹ to R⁷ are as definedabove for general formula IA, IB and IC, unless noted otherwise. Optimumreaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC) or HPLC-MS ifdesired. Intermediates and products may be purified by chromatography onsilica gel, recrystallization, HPLC and/or reverse phase HPLC.

Starting materials and reagents are either commercially available or maybe prepared by one skilled in the art using methods described in thechemical literature and in the Synthetic Examples section below.

Compounds of formula IA may be prepared as shown in Scheme 1.

As illustrated in Scheme 1, a 1,2-diaminobenzene derivative substitutedwith R¹ and R² may be reacted with a pyridine aldehyde derivativesubstituted with R³-R⁷ to provide the desired compound of formula IA.The reaction may be run in acetic acid or in aqueous DMF in the presenceof oxone or alternatively, in a suitable solvent such as methanol, inthe presence of a suitable catalyst such as L-proline orp-toluenesulfonic acid.

Compounds of formula IB and IC may be prepared according to Scheme1, byusing the corresponding 3 or 4 pyridine aldehyde.

Diamino intermediate II may be prepared as illustrated in Schemes 2

In Scheme 2, a disubstituted nitro benzene of formula IV, is reactedwith an amine of formula V, in a suitable solvent, in the presence of asuitable base such as potassium carbonate, to provide an intermediate offormula VI. X is Cl or Br. Reaction of the intermediate of formula VIwith a boronic acid ester of formula VII, in a suitable solvent, in thepresence of a suitable catalyst, provides a coupled product of formulaVIII. Ra and Rb are hydrogen or Ra and Rb together with the oxygen atomsto which they are attached form a 5-6 membered ring optionallysubstituted with 2-4 methyl groups. Reduction of nitro compound VIIIprovides an intermediate of formula II.

Intermediate III having R³ being a nitrogen containing heteroarylconnected to the pyridine ring by the nitrogen, may be prepared asillustrated in Scheme 3.

In Scheme 3, reaction of a substituted pyridine aldehyde of formula IXwith a boronic acid of formula X or a boronic ester bearing R⁶, in asuitable solvent, in the presence of a catalyst, provides anintermediate of formula XI. Compound of formula XI is reacted with aheteroaryl group having a NH in the ring, for example triazole XII, inthe presence of a suitable base such as potassium carbonate in asuitable solvent such as DMSO to provide the desired intermediate offormula III (R³=triazole).

Intermediate III may also be prepared according to Scheme 4.

As shown in Scheme 4, bromination of a substituted pyridine of formulaXIII with a reagent such as NBS and benzoyl peroxide, in a suitablesolvent, provides a bromo compound of formula XIV. Further reaction ofcompound XIV with N-methylmorpholine-N-oxide, in a suitable solvent,provides a compound of formula III.

Compounds of formula IB and IC may be made by methods outlined inschemes 1-4 by using the appropriately pyridine aldehyde correspondingto intermediate III.

Compounds of formula IA, IB, IC as well as the respective intermediatesprepared by the above methods may be further converted to additionalintermediates or compounds of formula IA, IB and IC by methods known inthe art and exemplified in the Synthetic Examples section below.

SYNTHETIC EXAMPLES Synthesis of Intermediates4-(2-Amino-pyrimidin-5-yl)-N-1-tert-butyl-benzene-1,2-diamine

To a solution of R-1 (25 g, 0.1 mol) in THF (100 mL) is added R-2 (18mL, 0.17 mol). The solution is heated at 60° C. for 16 hours. Thesolvent is removed in vacuum. The residue is suspended in methanol (20mL). The precipitate is collected by filtration and washed with methanolto give R-3.

To a solution of R-3 (7.2 g, 0.026 mol) in DMF (100 mL) and H₂O (10 mL)are added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-ylamine (8.7g, 0.04 mol), Pd(PPh₃)₄ (3 g, 0.003 mol) and K₂CO₃ (7.3 g, 0.053 mol) atroom temperature. The solution is heated to 100° C. for 2 hours. Thesolution is cooled down, washed with H₂O (100 mL) and extracted withEtOAc. The combined organic layer is dried with MgSO₄ and filtered. Thefiltrate is concentrated and the residue is re-crystallized in CH₂Cl₂ toafford R-4.

To a round bottom flask are added R-4 (6.3 g, 0.02 mol) and ammoniumformate (6.9 g, 0.1 mol) in EtOH, (100 mL), followed by the addition ofzinc dust (4.3 g, 0.066 mol). The reaction mixture is stirred at 50° C.for 2 hours. The reaction mixture is filtered through a short pad ofdiatomaceous earth. The filter pad is rinsed with MeOH (50 mL) and thecombined filtrate is concentrated. The residue is extracted with H₂O (50mL) and EtOAc (3×50 mL). The combined organic layer is washed withsaturated NaHCO₃ solution, dried (MgSO₄) and filtered. The filtrate isconcentrated to afford the title intermediate I-1 (4.5 g).

The following intermediates were synthesized in similar fashion from theappropriate reagents:

Intermediate Structure I-2

I-3

6-Cyclopropyl-3-1,2,4-triazol-1-yl-pyridine-2-carbaldehyde

R-5 (2.20 g, 10.78 mmol) is combined with R-8 (1.20 g, 14.02 mmol),tribasic potassium phosphate (8.01 g, 37.75 mmol) andtricyclohexylphosphine (0.30 g, 1.08 mmol) and diluted with toluene (40ml) and water (2 ml). The palladium acetate is added (0.24 g, 1.08 mmol)and the mixture is sonicated for five minutes and then degassed withnitrogen. The reaction is warmed to 100° C. for 22 hours, cooled toambient temperature and poured into water. The product is extracted intoethyl acetate and the organics are dried with MgSO₄, filtered andconcentrated. The residue is purified by silica gel flash columnchromatography with 5-40% ethyl acetate in heptane as the eluent toafford R-9. R-9 (250 mg, 1.51 mmol) in DMSO (10 ml) is treated with1,2,4-triazole (125 mg, 1.82 mmol) and potassium carbonate (420 mg, 3.03mmol). The resulting mixture is warmed to 80° C. for 5 minutes in amicrowave reactor. The reaction is poured into water and the product isextracted into ethyl acetate. The combined organics are dried withMgSO₄, filtered and concentrated. The residue is purified by silica gelflash column chromatography with 5-100% ethyl acetate in heptane as theeluent to give the title intermediate 1-4 (175 mg).

6-Cyano-2-formyl-nicotinic acid methyl ester

To a solution of R-10 (300 mg, 1.98 mmol) in CH₂Cl₂ (10 ml) is addedmCPBA (890 mg, 3.97 mmol) at room temperature. The solution is stirredat the same temperature for 24 hours. The solution is filtered and thefiltrate is concentrated. The residue is purifed by silica gel flashcolumn chromatography with 10% MeOH in CH₂Cl₂ as the eluent to affordR-11 as a white solid.

To a solution of R-11 (527 mg, 3.13 mmol) in CH₂Cl₂ (10 ml) is addedtrimethylsilyl cyanide (622 mg, 6.27 mmol) and dimethylcarbamyl chloride(0.59 ml, 6.27 mmol) at room temperature. The solution is stirred at thesame temperature for 48 hours. The solution is concentrated and theresidue is purified by silica gel flash cloumn chromatography with 10%EtOAc in heptane as the eluent to afford R-12 as a colorless oil.

To a solution of R-12 (316 mg, 1.79 mmol) in CCl₄ (10 ml) is addedN-bromosuccinimide (639 mg, 3.59 mmol) and benzoyl peroxide (869 mg,3.59 mmol) at room temperature. The mixture is heated at 100° C. for 6hours. The solution is cooled down and extracted with CH₂Cl₂ and H₂O.The combined organic layers are dried with MgSO₄ and filtered. Thefiltrate is concentrated and the residue purified by silica gel flashcolumn chromatography with 10% EtOAc in Heptane as the eluent to affordR-13 as a pale brown foam.

To a solution of R-13 (700 mg, 2.74 mmol) in CH₃CN (10 ml) is addedN-methylmorpholine-N-oxide (649 mg, 5.49 mmol) at room temperature. Thesolution is stirred at the same temperature for 12 hours. The solutionis concentrated and the residue purified by silica gel flash columnchromatography with 10% EtOAc in Heptane as the eluent to afford 1-5(500 mg) as an colorless oil.

2-Formyl-nicotinic acid methyl ester

To a solution of R-10 (300 mg, 1.98 mmol) in CCl₄ (10 ml) is addedN-bromosuccinimide (706 mg, 3.97 mmol) and benzoyl peroxide (720 mg,2.98 mmol) at room temperature. The mixture is heated at 100° C. for 6hours. The solution is cooled down and extracted with CH₂Cl₂ and H₂O.The combined organic layers are dried with MgSO₄ and filtered. Thefiltrate is concentrated and the residue purified by silica gel flashcolumn chromatography with 10% EtOAc in Heptane as the eluent to affordR-14 as a pale brown foam.

To a solution of R-14 (214 mg, 0.93 mmol) in CH₃CN (8 ml) is addedN-methylmorpholine-N-oxide (220 mg, 1.86 mmol) at room temperature. Thesolution is stirred at the same temperature for 12 hours. The solutionis concentrated and the residue purified by silica gel flash columnchromatography with 10% EtOAc in Heptane as the eluent to afford 1-6(140 mg) as an colorless oil.

2-1,2,4-Triazol-1-yl-pyridine-3-carbaldehyde

R-15 (200 mg, 1.41 mmol) and 1,2,4-triazole (127 mg, 1.84 mmol) arecombined in DMF (5 ml) and warmed to 70° C. for 16 hours. The reactionis cooled to room temperature and poured into water. The product isextracted into EtOAc and the combined organics are dried (MgSO₄),filtered and concentrated to afford 1-7 (160 mg).

The following intermediates were synthesized in similar fashion from theappropriate reagents:

Intermediate Strucuture I-8 

I-9 

I-10

I-11

I-12

6-Methyl-2-1,2,4-triazol-1-yl-pyridine-3-carbaldehyde

R-16 (1.00 g, 6.43 mmol) and 1,2,4-triazole (0.89 g, 12.86 mmol) arecombined in HOAc (15 ml) and warmed to 118° C. After 3 hours thereaction is cooled to room temperature and concentrated. The residue ispurified by silica gel flash column chromatography with 0-4% MeOH inCH₂Cl₂ as the eluent to afford I-13.

Synthesis of Final Compounds Method 1 Synthesis of6-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-5-(3-methyl-1,2,4-triazol-1-yl)-pyridine-2-carbonitrile(Example 2, Table 1)

To a solution of I-1 (500 mg, 1.94 mmol) in DMF (20 mL) is added R-5(396 mg, 1.94 mmol) followed by a solution of oxone (1.19 g, 1.94 mmol)in water (6 ml) at room temperature. The solution is stirred for 30minutes and poured into water (75 ml) and saturated aqueous sodiumthiosulfate (75 ml). The product is extracted into ethyl acetate and theorganics are dried with MgSO₄, filtered and concentrated. The residue ispurified by silica gel flash column chromatography with 10% MeOH inCH₂Cl₂ as the eluent to afford R-6.

R-6 (480 mg, 1.09 mmol) is dissolved in DMF (10 ml) and treated withzinc cyanide (130 mg, 1.09 mmol) andtetrakis(triphenylphosphine)palladium (0) (50 mg, 0.043 mmol). Thereaction is degassed using nitrogen, heated at 175° C. in a microwavereactor for 3 minutes and poured into water. The product is extractedinto ethyl acetate and the combined organics are dried over MgSO₄,filtered and concentrated. The residue is purified by silica gel flashcolumn chromatography with 10% MeOH in CH₂Cl₂ as the eluent to affordR-7.

R-7 (300 mg, 0.77 mmol) in DMSO (5 ml) is treated with3-methyl-1H-(1,2,4)-triazole (77 mg, 0.93 mmol) and potassium carbonate(210 mg, 1.55 mmol). The resulting mixture is warmed to 75° C. for 2hours and cooled to ambient temperature. The reaction is poured intowater and the product is extracted into ethyl acetate. The combinedorganics are dried with MgSO₄, filtered and concentrated. The residue issequentially purified by silica gel flash column chromatography with0-10% MeOH in CH₂Cl₂ as the eluent and reverse phase HPLC with 22%acetonitrile (0.1% TFA) in water (0.1% TFA) to give 2 (90 mg).

The following compounds were synthesized in similar fashion from theappropriate intermediates:

Example 1, Table 1

Example 3, Table 1

Example 5, Table 1

Example 6, Table 1

Method 2 Synthesis of5-[1-tert-Butyl-2-(6-cyclopropyl-3-1,2,4-triazol-1-yl-pyridin-2-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine(Example 4, Table 1)

To a solution of I-1 (210 mg, 0.82 mmol) in DMF (10 mL) is added 1-4(175 mg, 0.82 mmol) followed by a solution of oxone (500 mg, 0.82 mmol)in water (2 ml) at room temperature. The solution is stirred for 30minutes and poured into water (40 ml) and saturated aqueous sodiumthiosulfate (25 ml). The product is extracted into ethyl acetate and theorganics are dried with MgSO₄, filtered and concentrated. The residue ispurified by silica gel flash column chromatography with 0-10% MeOH inCH₂Cl₂ as the eluent to give 4 (175 mg).

The following compounds were synthesized in similar fashion from theappropriate intermediates:

Example 7, Table 1

Example 9, Table 1

Examples 11-19, Table 1

Example 23, Table 1

Example 29-33, Table 1

Method 3 Synthesis of2-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-6-cyano-N-methyl-nicotinamide(Example 10, Table 1)

To a solution of methlyamine hydrochlorde (35 mg, 0.51 mmol) in drytoluene (10 ml) is added AlMe₃ (0.35 ml, 0.70 mmol) at room temperature.The solution is stirred at the same temperature for 15 minutes. 9 (100mg, 0.23 mmol) in toluene is added to the solution and it is heated at90° C. for 3 hours. The mixture is cooled down to room temperature andwater is added. The mixture is extracted with EtOAc and the combinedorganic layers are dried by MgSO₄ and filtered. The filtrate isconcentrated and the residue purified by silica gel flash columnchromatography with 10% MeOH in CH₂Cl₂ as the eluent to afford 10 (10mg) as a white foam.

The following compounds were synthesized in similar fashion from theappropriate intermediates:

Example 8, Table 1

Method 4 Synthesis of5-[1-tert-Butyl-2-(5-chloro-2-1,2,4-triazol-1-yl-pyridin-3-yl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine(Example 22, Table 1)

I-1 (210 mg, 0.81 mmol) and 1-9 (170 mg, 0.81 mmol) are combined inmethanol (5 ml) and warmed to 65° C. After 2 hours the reaction istreated with L-proline (20 mg, 0.20 mmol) and heated for 40 hours. Thereaction is cooled to room temperature and the solid is removed viafiltration. The solid is washed with methanol and the combined filtratesare concentrated. The remaining residue is purified via flash columnchromatography with 2-10% MeOH in CH₂Cl₂ as the eluent to afford 22 (70mg).

The following compounds were synthesized in similar fashion from theappropriate intermediates:

Example 20, Table 1

Example 21, Table 1

Example 24, Table 1

Example 25, Table 1

Example 27, Table 1

Example 28, Table 1

Method 5 Synthesis of5-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-6-1,2,4-triazol-1-yl-nicotinonitrile(Example 26, Table 1)

In a microwave reaction vessel is dissolved 23 (370 mg, 0.75 mmol) inDMF (5 ml). Zinc cyanide (89 mg, 0.75 mmol) is added, followed by thetetrakis (triphenylphosphine)palladium (0) (30 mg, 0.030 mmol). Thereaction is degassed with nitrogen and heated to 175° C. in a microwavefor 3 minutes. The reaction is poured into water and extracted withethyl acetate. The combined organics are dried (MgSO₄), filtered andconcentrated. The residue is purified by flash column chromatographywith 2-10% MeOH in CH₂Cl₂ as the eluent to afford 26 (60 mg).

TABLE 3 Final Compounds Example Retention m/z LC/MS # Structure Methodtime (min) [M + H]⁺ Method 1

1 1.3 437.2 A 2

1 1.1 451.2 B 3

1 1.1 451.2 B 4

2 1.3 452.4 C 5

1 1.4 463.4 A 6

1 0.9 463.2 E 7

2 1.2 403.4 A 8

3 1.1 402.4 A 9

2 1.3 428.4 A 10

3 1.2 427.4 A 11

2 6.0 375.6 D 12

2 1.0 345.2 A 13

2 6.7 417.7 D 14

2 6.1 363.6 D 15

2 7.0 472.6 D 16

2 1.1 375.2 B 17

2 1.3 393.2 A 18

2 1.3 345.5 C 19

2 6.3 425.5 D 20

4 1.0 412.2 B 21

4 1.0 430.2 B 22

4 1.1 446.2 B 23

2 1.3 492.0 A 24

4 1.2 426.2 A 25

4 1.2 426.2 A 26

5 1.2 437.2 A 27

4 1.3 504.0 A 28

4 1.2 426.2 A 29

2 5.6 375.6 D 30

2 1.0 430.2 A 31

2 1.0 345.2 A 32

2 1.1 375.2 B 33

2 1.2 389.2 B

Assessment of Biological Properties

1. Binding Assay

Compounds are assessed for the ability to bind to FLAP in a bindingassay that measures compound-specific displacement of an iodinated(¹²⁵I) FLAP inhibitor via a Scintillation Proximity Assay format(adapted from S. Charleson et al., Mol. Pharmacol., 1992, 41, 873-879).

Cell pellets produced from sf9 insect cells expressing recombinant humanFLAP protein are resuspended in buffer A [15 mM Tris-HCl (pH 7.5), 2 mMMgCl₂, 0.3 mM EDTA, 1 mM PMSF]. The cells are lysed with a Douncehomogenizer and the material is centrifuged at 10,000×g for 10 minutes.The supernatant is then collected and centrifuged at 100,000×g for 60minutes. To prepare membrane protein for an assay, an aliquot of the100,000×g pellet is resuspended in 1 ml of buffer A, Dounce homogenized,and finally subjected to polytron mixing (30 seconds). Membrane protein(25 μl, 5 μg) is mixed with WGA SPA beads (Amersham) and stirred for 1h. To an assay plate (Perkin Elmer FlexiPlate) is added 25 μl of testcompound prepared in Binding buffer [100 mM Tris (pH 7.5), 140 mM NaCl,5% glycerol, 2 mM EDTA, 0.5 mM TCEP, 0.05% Tween 20], 25 μl of[¹²⁵I]L-691,831 (an iodinated analog of MK-591, Charleson et al. Mol.Pharmacol., 41, 873-879, 1992) and finally 50 μl of the bead/proteinmixture. (final concentrations: beads, 200 μg/well; protein, 5 μg/well;[¹²⁵I] probe, 0 08 nM/well (17 nCi/well). The plates are shaken for 2 hbefore reading on a Microbeta plate reader. Non-specific binding isdetermined by the addition of 10 μM cold L-691,831 compound.

In general, the preferred potency range (IC₅₀) of compounds in the aboveassay is between 0.1 nM to 10 μM, the more preferred potency range is0.1 nM to 1 μM, and the most preferred potency range is 0.1 nM to 100nM.

2. Whole Blood Assay

Compounds are additionally tested in a human whole blood assay todetermine their ability to inhibit the synthesis of LTB₄ in a cellularsystem. Compounds are combined with heparinized human whole blood andincubated for 15 minutes at 37° C. Calcimycin (20 μM final, prepared inphosphate-buffered saline, pH 7.4) is then added and the mixture isincubated for another 30 minutes at 37° C. The samples are centrifugedfor 5 min at low speed (1500×g) and the plasma layer is removed. PlasmaLTB₄ concentrations are then measured using an antibody-based homogenoustime-resolved fluorescence method (CisBio, Bedford, Mass.).

In general, the preferred potency range (IC₅₀) of compounds in the aboveassay is between 10 nM to 10 μM, the more preferred potency range is 10nM to 1 μM.

Method of Use

The compounds of the invention are effective inhibitors of5-lipoxygenase activating protein (FLAP) and thus inhibit leukotrieneproduction. Therefore, in one embodiment of the invention, there isprovided methods of treating leukotriene-mediated disorders usingcompounds of the invention. In another embodiment, there is providedmethods of treating cardiovascular, inflammatory, allergic, pulmonaryand fibrotic diseases, renal diseases and cancer using compounds of theinvention.

Without wishing to be bound by theory, by inhibiting the activity ofFLAP, the compounds of the invention block the production of LTsresulting from the oxidation of arachidonic acid by 5-LO and subsequentmetabolism. Thus, the inhibition of FLAP activity is an attractive meansfor preventing and treating a variety of diseases mediated by LTs. Theseinclude:

Cardiovascular diseases including atherosclerosis, myocardialinfarction, stroke, aortic aneurysm, sickle cell crisis,ischemia-reperfusion injury, pulmonary arterial hypertension and sepsis;

Allergic diseases including asthma, allergic rhinitis, rhinosinusitis,atopic dermatitis and urticaria;

Fibrotic diseases including airway remodeling in asthma, idiopathicpulmonary fibrosis, scleroderma, asbestosis;

Pulmonary syndromes including adult respiratory distress syndrome, viralbronchiolitis, obstructive sleep apnea, chronic obstructive pulmonarydisease, cystic fibrosis, and bronchopulmonary dysplasia;

Inflammatory diseases including rheumatoid arthritis, osteoarthritis,gout, glomerulonephritis, interstitial cystitis, psoriasis, inflammatorybowel disease systemic lupus erythematosus, transplant rejection,multiple sclerosis, inflammatory pain, inflammatory and allergic oculardiseases;

Cancer including solid tumors, leukemias and lymphomas; and

Renal diseases such as glomerulonephritis.

For treatment of the above-described diseases and conditions, atherapeutically effective dose will generally be in the range from about0.01 mg to about 100 mg/kg of body weight per dosage of a compound ofthe invention; preferably, from about 0.1 mg to about 20 mg/kg of bodyweight per dosage. For example, for administration to a 70 kg person,the dosage range would be from about 0.7 mg to about 7000 mg per dosageof a compound of the invention, preferably from about 7.0 mg to about1400 mg per dosage. Some degree of routine dose optimization may berequired to determine an optimal dosing level and pattern. The activeingredient may be administered from 1 to 6 times a day.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared using procedures well known in thepharmaceutical art and comprise at least one compound of the invention.The compounds of the invention may also be administered alone or incombination with adjuvants that enhance stability of the compounds ofthe invention, facilitate administration of pharmaceutical compositionscontaining them in certain embodiments, provide increased dissolution ordispersion, increased antagonist activity, provide adjunct therapy, andthe like. The compounds according to the invention may be used on theirown or in conjunction with other active substances according to theinvention, optionally also in conjunction with other pharmacologicallyactive substances. In general, the compounds of this invention areadministered in a therapeutically or pharmaceutically effective amount,but may be administered in lower amounts for diagnostic or otherpurposes.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted modes of administration of pharmaceutical compositions.Thus, administration can be, for example, orally, buccally (e.g.,sublingually), nasally, parenterally, topically, transdermally,vaginally, or rectally, in the form of solid, semi-solid, lyophilizedpowder, or liquid dosage forms, such as, for example, tablets,suppositories, pills, soft elastic and hard gelatin capsules, powders,solutions, suspensions, or aerosols, or the like, preferably in unitdosage forms suitable for simple administration of precise dosages. Thepharmaceutical compositions will generally include a conventionalpharmaceutical carrier or excipient and a compound of the invention asthe/an active agent, and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles,or combinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known to thoseof skill in the art. The state of the art is evidenced, e.g., byRemington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995;Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), AmericanPharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger, 1990; each of which is incorporated herein by reference intheir entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds ofthe invention utilized in a particular pharmaceutical formulation willbe selected (e.g., salts) that possess suitable physical characteristics(e.g., water solubility) that are required for the formulation to beefficacious.

1. A compound of formula IA wherein:

R¹ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl,imidazopyridinyl, pyrazolopyridinyl or dihydropyrrolopyridinyloptionally substituted with oxo, wherein each heterocycle is optionallyindependently substituted with one to three groups selected from Ra, Rband Rc; R² is C₁-C₆ alkyl or C₃₋₆ cycloalkyl optionally substituted withC₁₋₃ alkyl; R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸, —C(O)NR⁸R⁹or 5-6 membered heteroaryl ring which is optionally substituted withC₁₋₃ alkyl; R⁴, R⁵, and R⁶ are each independently selected from (a) —H,(b) —OH, (c) halogen, (d) —CN, (e) —CF₃, (f) C₁₋₆alkyl optionallysubstituted with one to three —OH, fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or—C(O)N(R⁸)(R⁹), (g) C₃₋₆ cycloalkyl (h) C₁₋₆alkoxy optionallysubstituted with one to three —OH, fluorine, —OC₁₋₆alkyl, or —OC₃₋₆cycloalkyl (i) —S(O)_(n)C₁₋₆alkyl, (j) —S(O)₂aryl (k) —S(O)₂ heterocycle(l) —CO₂R⁸, (m) —SCF, (n′) a 5-6 membered heterocyclic ring; R⁸ and R⁹are each independently selected from —H, C₁₋₆alkyl, and 5-6 memberedheterocyclic ring; Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl,—NR¹⁰R¹¹, —NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆ alkyl,—S(O)₂—C₁-C₆alkyl, and —CH₂—OH; Rb is selected from —H, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH, —C≡N, —CH₂NH₂ and —C(O)OCH₃; Rc isselected from —H, —CH₃ and —OH; R¹⁰ and R¹¹ are each independentlyselected from —H, C₁₋₆alkyl, C₁₋₆alkyl-5-6 membered heterocyclyl,C₁₋₆alkyl-5-6 membered heteroaryl optionally substituted with halogenand C₁₋₆ alkyl-aryl; n is 0, 1 or 2; or a pharmaceutically acceptablesalt thereof.
 2. A compound of formula (IA) according to claim 1, or apharmaceutically acceptable salt thereof, wherein: R¹ is selected from:

R² is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl,pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the cycloalkyl group is optionally substituted with a C₁₋₃ alkylgroup; R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸, —C(O)NR⁸R⁹,pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein the heteroaryl ring isoptionally substituted with C₁₋₃ alkyl; R⁴, R⁵ and R⁶ are eachindependently selected from (a) —H, (b) —OH, (c) halogen, (d) —CN, (e)—CF₃, (f) C₁₋₆alkyl optionally substituted with one to three —OH,fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹), (g) C₃₋₆ cycloalkyl(h) C₁₋₆alkoxy optionally substituted with one to three —OH, fluorine,—OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl (i) —S(O)_(n)C₁₋₆alkyl, (j) —S(O)₂aryl(k) —S(O)₂ heterocycle (l) —CO₂R⁸, (m) —SCF, (n′) a pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl,thiomorpholinyl, dioxothiomorpholinyl and tetrahydropyranyl; R⁸ and R⁹are each independently selected from —H, C₁₋₆alkyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl,thiomorpholinyl, dioxothiomorpholinyl and tetrahydropyranyl; Ra isselected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹, —NH—C(O)C₁-C₆alkyl,NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl, —O(C₃-C₆)cycloalkyl,—S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl, —S(O)₂—C₁-C₆alkyl and —CH₂—OH; Rb isselected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH, —C≡N,—CH₂NH₂ and —C(O)OCH₃; Rc is selected from —H, —CH₃ and, —OH; R¹⁰ andR¹¹ are each independently selected from —H, C₁₋₆alkyl, C₁₋₆alkyl-5-6membered heterocyclyl, C₁₋₆alkyl-5-6 membered heteroaryl optionallysubstituted with fluoro and C₁₋₆alkyl-phenyl; n is 0, 1 or
 2. 3. Acompound of formula (IA) according to claim 1, wherein: R¹ is selectedfrom:

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl and —CH₂—OH; Rb is selected from —H, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH, —C≡N, —CH₂NH₂ and —C(O)OCH₃; Rc isselected from —H, —CH₃ and, —OH; R¹⁰ and R¹¹ are each independentlyselected from —H, C₁₋₆alkyl, C₁₋₆alkyl-5-6 membered heterocyclyl,C₁₋₆alkyl-fluorpyridine and C₁₋₆alkyl-phenyl; or a pharmaceuticallyacceptable salt thereof.
 4. A compound of formula (IA) according toclaim 1, wherein: R² is methyl, ethyl, propyl, isopropyl, butyl,t-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein thecycloalkyl group is optionally substituted with methyl; or apharmaceutically acceptable salt thereof.
 5. A compound of formula (IA)according to claim 1, wherein: R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy,—COOR⁸, —C(O)NR⁸R⁹, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl,triazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein theheteroaryl ring is optionally substituted with C₁₋₃ alkyl; R⁴, R⁵ and R⁶are each independently selected from (a) —H, (b) —OH, (c) halogen, (d)—CN, (e) —CF₃, (f) C₁₋₆alkyl optionally substituted with one to three—OH, fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹), (g) C₃₋₆cycloalkyl (h) C₁₋₆alkoxy optionally substituted with one to three —OH,fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl (i) —S(O)₂C₁₋₆alkyl, (j)—S(O)₂aryl (k)-5 (O)₂ heterocycle (l) —CO₂R⁸, (m) —SCF₃, (n′) apyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; R⁸ and R⁹ are each independently selected from —H,C₁₋₆alkyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; or a pharmaceutically acceptable salt thereof.
 6. Acompound of formula (IA) according to claim 1, wherein: R¹ is selectedfrom:

R² is t-butyl or cyclobutyl optionally substituted with a methyl group;R³ is —H, C₁₋₃ alkoxy, —COOR⁸, —C(O)NR⁸R⁹ or triazolyl which isoptionally substituted with a methyl group; R⁴, R⁵ and R⁶ are eachindependently selected from (a) —H, (b) —OH, (c) halogen, (d) —CN, (e)—CF₃, (f) C₁₋₆alkyl optionally substituted with one to three —OH,fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹), (g) C₃₋₆ cycloalkyl(h) C₁₋₆alkoxy optionally substituted with one to three —OH, fluorine,—OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl; R⁸ and R⁹ are each independentlyselected from —H and C₁₋₆alkyl; or a pharmaceutically acceptable saltthereof.
 7. A compound of formula (IA) according to claim 6, or apharmaceutically acceptable salt thereof, wherein: R¹ is


8. A compound of formula (IA) according to claim 6, wherein: R² ist-butyl or cyclobutyl optionally substituted with a methyl group; or apharmaceutically acceptable salt thereof.
 9. A compound of formula (IA)according to claim 6, wherein: R¹ is

R² is t-butyl; R³ is selected from

R⁴, R⁵ and R⁶ are each independently selected from —H, —CN, F,cyclopropyl, methoxy and t-butoxy; or a pharmaceutically acceptable saltthereof.
 10. A compound of formula (IA) according to claim 9, wherein:R² is

or a pharmaceutically acceptable salt thereof.
 11. A compound of formulaIB wherein:

R¹ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl,imidazopyridinyl, pyrazolopyridinyl or dihydropyrrolopyridinyloptionally substituted with oxo, wherein each heterocycle is optionallyindependently substituted with one to three groups selected from Ra, Rband Rc; R² is C₁-C₆ alkyl or C₃₋₆ cycloalkyl optionally substituted withC₁₋₃ alkyl; R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸, —C(O)NR⁸R⁹or 5-6 membered heteroaryl ring which is optionally substituted withC₁₋₃ alkyl; R⁵, R⁶, and R⁷ are each independently selected from (a) —H,(b) —OH, (c) halogen, (d) —CN, (e) —CF₃, (f) C₁₋₆alkyl optionallysubstituted with one to three —OH, fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or—C(O)N(R⁸)(R⁹), (g) C₃₋₆ cycloalkyl (h) C₁₋₆alkoxy optionallysubstituted with one to three —OH, fluorine, —OC₁₋₆alkyl, or —OC₃₋₆cycloalkyl (i) —S(O)_(n)C₁₋₆alkyl, (j) —S(O)₂aryl (k) —S(O)₂ heterocycle(l) —CO₂R⁸, (m) —SCF₃, (n′) a 5-6 membered heterocyclic ring; R⁸ and R⁹are each independently selected from —H, C₁₋₆alkyl, and 5-6 memberedheterocyclic ring; Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl,—NR¹⁰R¹¹, —NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl, and —CH₂—OH; Rb is selected from —H, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH, —C≡N, —CH₂NH₂ and —C(O)OCH₃; Rc isselected from —H, —CH₃ and, —OH; R¹⁰ and R¹¹ are each independentlyselected from —H, C₁₋₆alkyl, C₁₋₆alkyl-5-6 membered heterocyclyl,C₁₋₆alkyl-5-6 membered heteroaryl optionally substituted with halogenand C₁₋₆alkyl-aryl; n is 0, 1 or 2; or a pharmaceutically acceptablesalt thereof.
 12. A compound of formula (IB) according to claim 11, or apharmaceutically acceptable salt thereof, wherein: R¹ is selected from:

R² is methyl, ethyl, propyl, isopropyl, dimethylpropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the cycloalkyl group is optionally substituted witha C₁₋₃ alkyl group; R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸,—C(O)NR⁸R⁹, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl,triazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein theheteroaryl ring is optionally substituted with C₁₋₃ alkyl; R⁵, R⁶ and R⁷are each independently selected from (a) —H, (b) —OH, (c) halogen, (d)—CN, (e) —CF₃, (f) C₁₋₆alkyl optionally substituted with one to three—OH, fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹), (g) C₃₋₆cycloalkyl (h) C₁₋₆alkoxy optionally substituted with one to three —OH,fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl (i) —S(O)_(n)C₁₋₆alkyl, (j)—S(O)₂aryl (k) —S(O)₂heterocycle (l) —CO₂R⁸, (m) —SCF₃, (n′) apyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; R⁸ and R⁹ are each independently selected from —H,C₁₋₆alkyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl,—NR¹⁰R¹¹, —NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl, and —CH₂—OH; Rb is selected from —H, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH, —C≡N, —CH₂NH₂ and —C(O)OCH₃; Rc isselected from —H, —CH₃ and, —OH; R¹⁰ and R¹¹ are each independentlyselected from —H, C₁₋₆alkyl, C₁₋₆alkyl-5-6 membered heterocyclyl,C₁₋₆alkyl-fluoropyridine and C₁₋₆alkyl-phenyll; n is 0, 1 or
 2. 13. Acompound of formula (IB) according to claim 11, wherein: R¹ is selectedfrom:

Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹,—NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl and —CH₂—OH; Rb is selected from —H, —(C₁-C₆)alkyl,—O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH, —C≡N, —CH₂NH₂ and —C(O)OCH₃; Rc isselected from —H, —CH₃ and, —OH; R¹⁰ and R¹¹ are each independentlyselected from —H, C₁₋₆alkyl, C₁₋₆alkyl-5-6 membered heterocyclyl,C₁₋₆alkyl-fluoropyridine and C₁₋₆alkyl-phenyl; or a pharmaceuticallyacceptable salt thereof.
 14. A compound of formula (IB) according toclaim 11, wherein: R² is methyl, ethyl, propyl, isopropyl,dimethylpropyl, butyl, t-butyl or isobutyl; or a pharmaceuticallyacceptable salt thereof.
 15. A compound of formula (IB) according toclaim 11, wherein: R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸,—C(O)NR⁸R⁹, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl,triazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein theheteroaryl ring is optionally substituted with C₁₋₃ alkyl; R⁵, R⁶ and R⁷are each independently selected from (a) —H, (b) —OH, (c) halogen, (d)—CN, (e) —CF₃, (f) C₁₋₆alkyl optionally substituted with one to three—OH, fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹), (g) C₃₋₆cycloalkyl (h) C₁₋₆alkoxy optionally substituted with one to three —OH,fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl (i) —S(O)₂C₁₋₆alkyl, (i)—S(O)₂aryl (k)-5 (O)₂ heterocycle (l) —CO₂R⁸, (m) —SCF, (n′) apyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; R⁸ and R⁹ are each independently selected from —H,C₁₋₆alkyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; or a pharmaceutically acceptable salt thereof.
 16. Acompound of formula (IB) according to claim 11, wherein: R¹ is selectedfrom:

R² is t-butyl or dimethylpropyl; R³ is —H, C₁₋₃ alkoxy, or triazolylwhich is optionally substituted with a methyl group; R⁵, R⁶ and R⁷ areeach independently selected from (a) —H, (b) —OH, (c) halogen, (d) —CN,(e) —CF₃, (f) C₁₋₆alkyl optionally substituted with one to three —OH,fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹), (g) C₃₋₆ cycloalkyl,(h) C₁₋₆alkoxy optionally substituted with one to three —OH, fluorine,—OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl, (i) morpholinyl or piperidinyl; R⁸and R⁹ are each independently selected from —H and C₁₋₆alkyl; or apharmaceutically acceptable salt thereof.
 17. A compound of formula (IB)as described in claim 16, or a pharmaceutically acceptable salt thereof,wherein: R¹ is


18. A compound of formula (IB) as described in claim 16, wherein: R² ist-butyl or dimethylpropyl; or a pharmaceutically acceptable saltthereof.
 19. A compound of formula (IB) according to claim 16, wherein:R¹ is

R² is t-butyl or dimethylpropyl; R³ is selected from

R⁵, R⁶ and R⁷ are each independently selected from —H, —CN, F, Cl, Br,methyl, morpholinyl and methoxy; or a pharmaceutically acceptable saltthereof.
 20. A compound of formula (IB) according to claim 19, wherein:R² is t-butyl; R³ is selected from

R⁵, R⁶ and R⁷ are each independently selected from —H, methyl and Br; ora pharmaceutically acceptable salt thereof.
 21. A compound of formula IC

wherein: R¹ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridinyl ordihydropyrrolopyridinyl optionally substituted with oxo, wherein eachheterocycle is optionally independently substituted with one to threegroups selected from Ra, Rb and Rc; R² is C₁-C₆ alkyl or C₃₋₆ cycloalkyloptionally substituted with C₁₋₃ alkyl; R³ is H, —OH, halogen, —CN, C₁₋₆alkoxy, —COOR⁸, —C(O)NR⁸R⁹ or 5-6 membered heteroaryl ring which isoptionally substituted with C₁₋₃ alkyl; R⁴, R⁶, and R⁷ are eachindependently selected from (a) —H, (b) —OH, (c) halogen, (d) —CN, (e)—CF₃, (f) C₁₋₆alkyl optionally substituted with one to three —OH,fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹), (g) C₃₋₆ cycloalkyl(h) C₁₋₆alkoxy optionally substituted with one to three —OH, fluorine,—OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl (i) —S(O)_(n)C₁₋₆alkyl, (j) —S(O)₂aryl(k) —S(O)₂ heterocycle (l) —CO₂R⁸, (m) —SCF₃, (n′) a 5-6 memberedheterocyclic ring; R⁸ and R⁹ are each independently selected from —H,C₁₋₆alkyl, and 5-6 membered heterocyclic ring; Ra is selected from H,—NH₂, —NH(C₁-C₆)alkyl, —NR¹⁰R¹¹, —NH—C(O)C₁-C₆alkyl,NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl, —O(C₃-C₆)cycloalkyl,—S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl, —S(O)₂—C₁-C₆alkyl, and —CH₂—OH; Rb isselected from —H, —(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH, —C≡N,—CH₂NH₂ and —C(O)OCH₃; Rc is selected from —H, —CH₃ and, —OH; R¹⁰ andR¹¹ are each independently selected from —H, C₁₋₆alkyl, C₁₋₆alkyl-5-6membered heterocyclyl, C₁₋₆alkyl-5-6 membered heteroaryl optionallysubstituted with halogen and C₁₋₆alkyl-aryl; n is 0, 1 or 2; or apharmaceutically acceptable salt thereof.
 22. A compound of formula (IC)according to claim 21, or a pharmaceutically acceptable salt thereof,wherein: R¹ is selected from:

R² is methyl, ethyl, propyl, isopropyl, dimethylpropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, wherein the cycloalkyl group is optionally substituted witha C₁₋₃ alkyl group; R³ is H, —OH, halogen, —CN, C₁₋₆ alkoxy, —COOR⁸,—C(O)NR⁸R⁹, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl,triazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein theheteroaryl ring is optionally substituted with C₁₋₃ alkyl; R⁴, R⁶ and R⁷are each independently selected from (a) —H, (b) —OH, (c) halogen, (d)—CN, (e) —CF₃, (f) C₁₋₆alkyl optionally substituted with one to three—OH, fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹), (g) C₃₋₆cycloalkyl (h) C₁₋₆alkoxy optionally substituted with one to three —OH,fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl (i) —S(O)_(n)C₁₋₆alkyl, (j)—S(O)₂aryl (k) —S(O)₂ heterocycle (l) —CO₂R⁸, (m) —SCF₃, (n′) apyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; R⁸ and R⁹ are each independently selected from —H,C₁₋₆alkyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; Ra is selected from H, —NH₂, —NH(C₁-C₆)alkyl,—NR¹⁰R¹¹, —NH—C(O)C₁-C₆alkyl, NR¹¹—C(O)C₁-C₆alkyl, —O(C₁-C₈)alkyl,—O(C₃-C₆)cycloalkyl, —S—(C₁-C₆)alkyl, —S(O)—C₁-C₆alkyl,—S(O)₂—C₁-C₆alkyl, oxo and —CH₂—OH; Rb is selected from —H,—(C₁-C₆)alkyl, —O—(C₁-C₆)alkyl, —NH₂, —CH₂—OH, —C≡N, —CH₂NH₂ and—C(O)OCH₃; Rc is selected from —H, —CH₃ and, —OH; R¹⁰ and R¹¹ are eachindependently selected from —H, C₁₋₆alkyl, C₁₋₆alkyl-5-6 memberedheterocyclyl, C₁₋₆alkyl-fluoropyridine and C₁₋₆alkyl-phenyl; n is 0, 1or
 2. 23. A compound of formula (IC) as described in claim 21, wherein:R¹ is selected from:

or a pharmaceutically acceptable salt thereof.
 24. A compound of formula(IC) as described in claim 21, wherein: R² is methyl, ethyl, propyl,isopropyl, dimethylpropyl, butyl, t-butyl or isobutyl; or apharmaceutically acceptable salt thereof.
 25. A compound of formula (IC)as described in claim 21, wherein: R³ is H, —OH, halogen, —CN, C₁₋₆alkoxy, —COOR⁸, —C(O)NR⁸R⁹, pyrrolyl, furanyl, thienyl, imidazolyl,pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,wherein the heteroaryl ring is optionally substituted with C₁₋₃ alkyl;R⁴, R⁶ and R⁷ are each independently selected from (a) —H, (b) —OH, (c)halogen, (d) —CN, (e) —CF₃, (f) C₁₋₆alkyl optionally substituted withone to three —OH, fluorine, C₁₋₆alkoxyl-N(R⁸)(R⁹), or —C(O)N(R⁸)(R⁹),(g) C₃₋₆ cycloalkyl (h) C₁₋₆alkoxy optionally substituted with one tothree —OH, fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl (i)—S(O)₂C₁₋₆alkyl, (j) —S(O)₂aryl (k)-5 (O)₂ heterocycle (l) —CO₂R⁸, (m)—SCF₃, (n′) a pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; R⁸ and R⁹ are each independently selected from —H,C₁₋₆alkyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl andtetrahydropyranyl; or a pharmaceutically acceptable salt thereof.
 26. Acompound of formula (IC) as described in claim 21, wherein: R¹ isselected from:

R² is t-butyl; R³ is —H or halogen; R⁴, R⁶ and R⁷ are each independentlyselected from (a) —H, (b) —OH, (c) halogen, (d) —CN, (e) —CF₃, (f)C₁₋₆alkyl; (g) C₃₋₆ cycloalkyl, (h) C₁₋₆alkoxy optionally substitutedwith one to three —OH, fluorine, —OC₁₋₆alkyl, or —OC₃₋₆ cycloalkyl; or apharmaceutically acceptable salt thereof.
 27. A compound of formula (IC)as described in claim 26, or a pharmaceutically acceptable salt thereof,wherein R¹ is


28. A compound of formula (IC) as described in claim 26, wherein: R² ist-butyl; or a pharmaceutically acceptable salt thereof.
 29. A compoundof formula (IC) according to claim 26, wherein: R¹ is

R² is t-butyl; R³ is F; R⁴, R⁶ and R⁷ are each independently selectedfrom —H, Br and methoxy; or a pharmaceutically acceptable salt thereof.30. A compound selected from a group consisting of:

or pharmaceutically acceptable salts thereof.
 31. A compound accordingto claim 30, selected from a group consisting of:

or pharmaceutically acceptable salts thereof.
 32. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient and/or carrier.
 33. A method of treating aleukotriene-mediated disorder comprising administering an effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.
 34. The method ofclaim 33, wherein said leukotriene-mediated disorder is selected fromcardiovascular, inflammatory, allergic, pulmonary and fibrotic diseases,renal diseases and cancer.
 35. The method of claim 34, wherein saidleukotriene-mediated disorder is Atherosclerosis.
 36. A pharmaceuticalcomposition comprising a compound according to claim 11, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient and/or carrier.
 37. A pharmaceutical compositioncomprising a compound according to claim 21, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipientand/or carrier.